18-46529227-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001384474.1(LOXHD1):c.4480C>T(p.Arg1494*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,551,550 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1494R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

LOXHD1
NM_001384474.1 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23O:1

Conservation

PhyloP100: 2.00

Publications

25 publications found

Variant links:

Genes affected

LOXHD1 (HGNC:26521): (lipoxygenase homology PLAT domains 1) This gene encodes a highly conserved protein consisting entirely of PLAT (polycystin/lipoxygenase/alpha-toxin) domains, thought to be involved in targeting proteins to the plasma membrane. Studies in mice show that this gene is expressed in the mechanosensory hair cells in the inner ear, and mutations in this gene lead to auditory defects, indicating that this gene is essential for normal hair cell function. Screening of human families segregating deafness identified a mutation in this gene which causes DFNB77, a progressive form of autosomal-recessive nonsyndromic hearing loss (ARNSHL). Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Mar 2010]

LOXHD1 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 77
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Fuchs' endothelial dystrophy
Inheritance: AD Classification: LIMITED Submitted by: Illumina

LOXHD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 18-46529227-G-A is Pathogenic according to our data. Variant chr18-46529227-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 178396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384474.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LOXHD1	NM_001384474.1	MANE Select	c.4480C>T	p.Arg1494*	stop_gained	Exon 29 of 41	NP_001371403.1	A0A2R8Y7K4
LOXHD1	NM_144612.7		c.4480C>T	p.Arg1494*	stop_gained	Exon 29 of 40	NP_653213.6
LOXHD1	NM_001145472.3		c.1147C>T	p.Arg383*	stop_gained	Exon 11 of 24	NP_001138944.1	Q8IVV2-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LOXHD1	ENST00000642948.1	MANE Select	c.4480C>T	p.Arg1494*	stop_gained	Exon 29 of 41	ENSP00000496347.1	A0A2R8Y7K4
LOXHD1	ENST00000300591.11	TSL:1	c.1147C>T	p.Arg383*	stop_gained	Exon 11 of 24	ENSP00000300591.6	Q8IVV2-3
LOXHD1	ENST00000579038.6	TSL:1	c.859C>T	p.Arg287*	stop_gained	Exon 9 of 22	ENSP00000463285.1	J3QKX9

Frequencies

GnomAD3 genomes

AF:

0.000625

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.000661

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00112

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000611

AC:

AN:

158746

AF XY:

0.000550

show subpopulations

Gnomad AFR exome

AF:

0.000114

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.000822

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000709

Gnomad NFE exome

AF:

0.00108

Gnomad OTH exome

AF:

0.000446

GnomAD4 exome

AF:

0.00108

AC:

1514

AN:

1399408

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

720

AN XY:

690212

show subpopulations

African (AFR)

AF:

0.000158

AC:

AN:

31596

American (AMR)

AF:

0.000252

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.000437

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35736

South Asian (SAS)

AF:

0.000151

AC:

AN:

79232

European-Finnish (FIN)

AF:

0.000751

AC:

AN:

49284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00130

AC:

1405

AN:

1078962

Other (OTH)

AF:

0.000603

AC:

AN:

58014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

195

293

390

488

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000624

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41504

American (AMR)

AF:

0.0000655

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000208

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.000661

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00112

AC:

AN:

68016

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000888

Hom.:

Bravo

AF:

0.000593

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000723

AC:

ESP6500EA

AF:

0.00157

AC:

ExAC

AF:

0.000483

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive nonsyndromic hearing loss 77 (13)

not provided (6)

Nonsyndromic genetic hearing loss (2)

Inborn genetic diseases (1)

LOXHD1-related disorder (1)

Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.85

PhyloP100

2.0

Vest4

0.48

GERP RS

4.2

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over